Mitochondria conduct many reactions in eukaryotes. In particular, ATP synthesis via electron transport chain is important for organisms. Most ATP in cells is supplied by mitochondria. Other reaction systems in mitochondria relate to the TCA cycle, the heme synthesis system, the β oxidation cycle for fatty acids, the cycle for amino acid metabolism, and the like. Moreover, functions for maintaining Ca homeostasis, an active oxygen production system, and transport systems for metabolites, ions, proteins, and the like are present in mitochondria. Hence, mitochondria are intracellular organelles playing important roles in catabolic action and anabolic action in eukaryotes.
One thousand (1000) to 1500 types of protein are inferred to be present in human mitochondria. Thirteen (13) types thereof are proteins that are encoded by mitochondrial DNA and are subunits in electron transport chains. The other proteins, accounting for about 99%, are encoded by nuclear DNA. These proteins translocate to mitochondria after protein synthesis in cytoplasm. According to proteomic analysis, approximately 544 types of protein among the proteins existing in human mitochondria have been identified (Reichert A S and Neupert W., “Trends in Genetics,” 2004, Vol. 20, No. 11, p. 556-562). However, many unknown proteins are inferred to be present.
As described above, mitochondrial DNA encodes some subunits of complexes I, III, IV, and V in electron transport chains. Specifically, mutation in mitochondrial DNA causes dysfunction of electron transport chains. Examples of diseases relating to dysfunction of electron transport chains include MELAS, MERRF, cardiomyopathy, LHON, and Leigh encephalopathy. Nucleotide mutation in mitochondrial DNA has also been observed in early cancer of the liver, the prostate gland, the bladder, and the head and neck, primary lung cancer, and Barrett's esophagus (Verma M. et al., “Nature reviews cancer,” 2003, Vol. 3, No. 10, p. 789-795).
Meanwhile, abnormalities in mitochondrial proteins encoded by nuclear DNA cause many diseases as shown below: for example, (i) Friedreich's ataxia is caused by an abnormality in frataxin protein involved in Fe-S protein biosynthesis in mitochondria; (ii) an abnormality in Deafness dystonia peptide 1 (DDP1), which is a factor involved in protein translocation to mitochondria, is involved in Mohr-Tranebjaerg syndrome; (iii) retinal atrophy exhibiting autosomal dominant inheritance is caused by an abnormality in an OPA1 protein that causes mitochondrial membrane fusion; (iv) an abnormality in Mfn2, which is another factor involved in mitochondrial membrane fusion, causes the development of Charcot-Marie-Tooth neuropathy type 2; and (v) furthermore, an abnormality in thymidine phosphorylase of mitochondria causes the development of MNGIE (mitochondrial neuro gastrointestinal encephalomyopathy) exhibiting autosomal recessive inheritance and causing serious gastrointestinal symptoms.
In addition to the above involvement, involvement of mitochondrial dysfunction in more general diseases has also been demonstrated. For example, abnormalities in sugar metabolism and lipid metabolism due to mitochondrial dysfunction cause obesity, diabetes, and the like. Furthermore, a decreased intracellular ATP level due to mitochondrial dysfunction is a major factor of the cause of diseases such as Parkinson's disease and Alzheimer's disease. In recent years, it has also been reported that in Alzheimer's disease, amyloid β protein, which is an accumulated substance, binds intracellularly to an ABAD protein, which is a mitochondrial protein, so as to interfere with mitochondrial functions (Lustbader, J. W. et al., “Science,” 2004, Vol. 304, No. 5669, p. 448-452).
It is known that 0.4% to 4% oxygen to be consumed by mitochondria becomes active oxygen via electron transport chains. Such active oxygen is thought to damage DNA, proteins, and the like so as to cause cell injuries, decreased cell counts, and the like, thereby promoting hypofunction in cells or aging of individual organisms.
Furthermore, mitochondria are involved in apoptosis induction and the pathway is thought to be associated with cell growth and malignant transformation (canceration).
Therefore, it is extremely important to maintain normal mitochondrial functions and to control the functions successfully, not only for antiaging, but also for maintenance of the homeostasis of an individual organism's body.
Meanwhile, a protein called prohibitin (hereinafter, referred to as “PHB”) has been isolated from a mammal for the first time as a cell growth-suppressing factor. PHB is a protein that is highly conserved in organisms from yeast to mammals. It is known that in the PHB protein, 2 types of protein (PHB1 and PHB2, having primary amino acid structures analogous to each other) are present, form a complex, and are localized in the mitochondrial inner membrane. Yeast PHB proteins have been revealed to exert chaperone-like functions responsible for cell cycle control and stabilization of newly synthesized mitochondrial proteins (Berger, K. H. and Yaffe, M. P., “Mol Cell Biol.,” 1998, Vol. 18, No. 7, p. 4043-4052; Nijtmans, L. G. et al., “EMBO J.,” 2000, Vol. 19, No. 11, p. 2444-2451; and Piper P. W. and Bringloe, D., “Meth Ageing Dev.,” 2002, Vol. 123, No. 4, p. 287-295). Moreover, in Caenorhabditis elegans, involvement of PHB1 in aging and early development has been reported (Artal-Sanz M. et al., “J Biol Chem.,” 2003, Vol. 278, No. 34, p. 32091-32099).
Meanwhile, in mammals, various functions of PHB1 and PHB2, such as transcriptional control, have been suggested; however, their physiological functions in mitochondria have not yet been revealed (Delage-Mourroux R. et al., “J Biol Chem.,” 2000, Vol. 275, No. 46, p. 35848-35856; and Sun L. et al., “J Cell Sci.,” 2004, Vol. 117, p. 3021-3029).